N-sulfonylurea apoptosis promoters

ABSTRACT

Compounds having the formula  
                 
 
     are apoptosis promoters. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/366,442, filed Mar. 21, 2002.

TECHNICAL FIELD

[0002] The present invention relates to substituted N-sulfonylureaswhich are useful for promoting apoptosis, methods of making thecompounds, compositions containing the compounds, and methods oftreatment using the compounds.

BACKGROUND OF THE INVENTION

[0003] Apoptosis is a mode of cell death in which the cell commitssuicide either to ensure proper development of the organism or todestroy cells that represent a threat to the organism's integrity.Morphologically, apoptosis is characterized by blebbing of the plasmamembrane, shrinking of the cytoplasm and nucleus, and fragmenting intoparticles which are engulfed by phagocytic cells. Although apoptosisplays a critical role in normal development, its impairment is thoughtto be a significant factor in the etiology of such diseases as cancer,autoimmune disorders, inflammatory diseases, and viral infections.Conversely, increased apoptosis has been linked to AIDS andneurodegenerative diseases such as Parkinson's disease, stroke, andAlzheimer's disease.

[0004] Bcl-X_(L) is a protein which, in healthy cells, is expressed inthe outer membranes of the mitochondria, the endoplasmic reticulum, andthe nuclear envelope. Its function is to bind to specificprotein/protease complexes and prevent cell apoptosis. Upon internaldamage to the cell the protein/protease complexes are released, andcause the process of apoptosis to begin. An over-expression ofBcl-X_(L), often present in cancerous and other diseased cells, resultsin the blocking of apoptotic signals and allows the cells toproliferate. It is believed that by blocking BCl-X_(L), apoptosis can beinduced in diseased cells, and can provide an effective therapy forcancer and other diseases caused by the impairment of the apoptoticprocess. Based on these findings and the absence of small moleculeBCl-X_(L) inhibitors from current cancer therapies, there is acontinuing need for compounds which can trigger apoptosis through theinhibition of the Bcl family of proteins.

SUMMARY OF THE INVENTION

[0005] In its principle embodiment, the present invention provides acompound of formula (I)

[0006] or a therapeutically acceptable salt thereof, wherein

[0007] A is a five-, six-, or seven-membered non-aromatic ringcontaining a nitrogen atom wherein from zero to two carbon atoms arereplaced by a heteroatom selected from the group consisting of nitrogen,oxygen, and sulfur;

[0008] R¹ is selected from the group consisting of alkyl, cyano, halo,haloalkyl, nitro, and —NR⁵R⁶;

[0009] R², and R³ are independently selected from the group consistingof hydrogen, alkenyl, alkoxy, alkyl, alkylcarbonyloxy, alkylsulfanyl,alkynyl, aryl, arylalkoxy, aryloxy, aryloxyalkoxy, arylsulfanyl,arylsulfanylalkoxy, cycloalkylalkoxy, cycloalkyloxy, halo, haloalkoxy,haloalkyl, heterocycle, (heterocycle)oxy, hydroxy, nitro, and —NR⁵R⁶;

[0010] R⁴ is selected from the group consisting of aryl, arylalkenyl,arylalkoxy, cycloalkenyl, cycloalkyl, halo, heterocycle, and(heterocycle)alkoxy;

[0011] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl,arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl,heterocycle, (heterocycle)alkyl, (heterocycle)sulfanylalkyl,hydroxyalkyl, and a nitrogen protecting group; or

[0012] R⁵ and R⁶, together with the nitrogen atom to which they areattached, form a ring selected from the group consisting of imidazolyl,morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl,thiomorpholinyl, and thiomorpholinyl dioxide; and

[0013] R¹⁵ is selected from the group consisting of hydrogen, alkoxy,alkyl, and halo.

[0014] In another embodiment, the present invention discloses apharmaceutical composition comprising a compound of formula (I), or atherapeutically acceptable salt thereof, in combination with atherapeutically acceptable carrier.

[0015] In another embodiment, the present invention discloses a methodof promoting apoptosis in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of formula (I), or a therapeutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Compounds of the present invention comprise substitutedarylsulfonamides which are useful for the treatment ofapoptosis-mediated diseases.

[0017] As used in the present specification the following terms have themeanings indicated:

[0018] The term “alkenyl,” as used herein, represents a straight orbranched chain group of one to twelve carbon atoms derived from astraight or branched chain hydrocarbon containing at least onecarbon-carbon double bond.

[0019] The term “alkenylene,” as used herein, represents a group of twoto six atoms derived from an unsaturated straight or branched chainhydrocarbon.

[0020] The term “alkoxy,” as used herein, represents an alkyl groupattached to the parent molecular moiety through an oxygen atom.

[0021] The term “alkoxyalkoxy,” as used herein, represents an alkoxygroup attached to the parent molecular moiety through another alkoxygroup.

[0022] The term “alkoxyalkoxyalkyl,” as used herein, represents analkoxyalkoxy group attached to the parent molecular moiety through analkyl group.

[0023] The term “alkoxyalkoxycarbonyl,” as used herein, represents analkoxyalkoxy group attached to the parent molecular moiety through acarbonyl group.

[0024] The term “alkoxyalkyl,” as used herein, represents an alkoxygroup attached to the parent molecular moiety through an alkyl group.

[0025] The term “alkoxyalkylcarbonyl,” as used herein, represents analkoxyalkyl group attached to the parent molecular moiety through acarbonyl group.

[0026] The term “alkoxycarbonyl,” as used herein, represents an alkoxygroup attached to the parent molecular moiety through a carbonyl group.

[0027] The term “alkoxycarbonylalkyl,” as used herein, represents analkoxycarbonyl group attached to the parent molecular moiety through analkyl group.

[0028] The term “alkyl,” as used herein, represents a group of one totwelve carbon atoms derived from a straight or branched chain saturatedhydrocarbon.

[0029] The term “alkylamino,” as used herein, represents —N(R¹⁴)₂,wherein R¹⁴ is alkyl.

[0030] The term “alkylaminoalkyl,” as used herein, represents analkylamino group attached to the parent molecular moiety through analkyl group.

[0031] The term “alkylaminocarbonyl,” as used herein, represents analkylamino group attached to the parent molecular moiety through acarbonyl group.

[0032] The term “alkylaminocarbonylalkyl,” as used herein, represents analkylaminocarbonyl group attached to the parent molecular moiety throughan alkyl group.

[0033] The term “alkylcarbonyl,” as used herein, represents an alkylgroup attached to the parent molecular moiety through a carbonyl group.The alkylcarbonyl groups of this invention can be optionally substitutedwith one or two groups independently selected from the group consistingof hydroxy and —NR⁵R⁶, wherein R⁵ and R⁶ are as previously defined.

[0034] The term “alkylcarbonylalkyl,” as used herein, represents analkylcarbonyl group attached to the parent molecular moiety through analkyl group.

[0035] The term “alkylcarbonyloxy,” as used herein, represents analkylcarbonyl group attached to the parent molecular moiety through anoxygen atom.

[0036] The term “alkylene,” as used herein, represents a group of two tosix atoms derived from a saturated straight or branched chainhydrocarbon.

[0037] The term “alkylidene,” as used herein, refers to an alkenyl groupin which one carbon atom of the carbon-carbon double bond belongs to themoiety to which the alkenyl group is attached.

[0038] The term “alkylsulfanyl,” as used herein, represents an alkylgroup attached to the parent molecular moiety through a sulfur atom.

[0039] The term “alkylsulfanylalkyl,” as used herein, represents analkylsulfanyl group attached to the parent molecular moiety through analkyl group.

[0040] The term “alkylsulfonyl,” as used herein, represents an alkylgroup attached to the parent molecular moiety through a sulfonyl group.

[0041] The term “alkylsulfonylalkyl,” as used herein, represents analkylsulfonyl group attached to the parent molecular moiety through analkyl group.

[0042] The term “alkynyl,” as used herein, represents a straight orbranched chain group of one to twelve carbon atoms containing at leastone carbon-carbon triple bond.

[0043] The term “amino,” as used herein, represents —NR⁹R¹⁰, wherein R⁹and R¹⁰ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl,alkyl, alkylaminoalkyl, alkylaminocarbonylalkyl, alkylcarbonyl, aryl,arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl,arylsulfonyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl,haloalkyl, haloalkylcarbonyl, heterocycle, (heterocycle)alkyl,heterocyclecarbonyl, hydroxyalkyl, a nitrogen protecting group,—C(NH)NH₂, and —C(O)(CH₂)_(n)NR⁵R⁶, wherein n is 0, 1, 2, or 3; and R⁵and R⁶ are as previously defined; wherein the aryl; the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, and the arylsulfonyl; the cycloalkyl; the cycloalkyl partof the (cycloalkyl)alkyl and the cycloalkylcarbonyl; the heterocycle;and the heterocycle part of the (heterocycle)alkyl and theheterocyclecarbonyl can be optionally substituted with one, two, three,four, or five substituents independently selected from the groupconsisting of alkoxy, alkyl, alkylcarbonyl, cyano, halo, haloalkoxy,haloalkyl, hydroxy, and nitro.

[0044] The term “aminoalkoxy,” as used herein, represents an amino groupattached to the parent molecular moiety through an alkoxy group.

[0045] The term “aminoalkyl,” as used herein, represents an amino groupattached to the parent molecular moiety through an alkyl group.

[0046] The term “aminoalkylcarbonyl,” as used herein, represents anamino group attached to the parent molecular moiety through analkylcarbonyl group.

[0047] The term “aminocarbonyl,” as used herein, represents an aminogroup attached to the parent molecular moiety through a carbonyl group.

[0048] The term “aminocarbonylalkyl,” as used herein, represents anaminocarbonyl group attached to the parent molecular moiety through analkyl group.

[0049] The term “aminosulfonyl,” as used herein, represents an aminogroup attached to the parent molecular moiety through a sulfonyl group.

[0050] The term “aryl,” as used herein, represents a phenyl group or abicyclic or tricyclic fused ring system wherein one or more of the fusedrings is a phenyl group. Bicyclic fused ring systems are exemplified bya phenyl group fused to a monocyclic cycloalkyl group as defined herein,a monocyclic cycloalkenyl group as defined herein, or another phenylgroup. Tricyclic fused ring systems are exemplified by a bicyclic fusedring system fused to a monocyclic cycloalkyl group as defined herein, amonocyclic cycloalkenyl group as defined herein, or another phenylgroup. Representative examples of aryl include, but are not limited to,anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl,and tetrahydronaphthyl. Aryl groups having an unsaturated or partiallysaturated ring fused to an aromatic ring can be attached through thesaturated or the unsaturated part of the group. The aryl groups of thisinvention can be optionally substituted with one, two, three, four, orfive substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl,amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, asecond aryl group, arylalkoxy, aryloxy, arylsulfanyl, cyano, halo,haloalkoxy, haloalkyl, heterocycle, (heterocycle)alkyl,heterocyclecarbonylalkenyl, heterocyclecarbonylalkyl, hydroxy,hydroxyalkyl, nitro, oxo, and —C(NH)NH₂, wherein the second aryl group;the aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl; theheterocycle; and the heterocycle part of the (heterocycle)alkyl, theheterocyclecarbonylalkenyl, and the heterocyclecarbonylalkyl can befurther optionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkoxyalkylcarbonyl,alkoxycarbonyl, alkyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl,cyano, halo, haloalkoxy, haloalkyl, hydroxy, nitro, oxo, and —C(NH)NH₂.In addition, the heterocycle and the heterocycle part of the(heterocycle)alkyl, the heterocyclecarbonylalkenyl, and theheterocyclecarbonylalkyl can be further optionally substituted with anadditional aryl group, wherein the additional aryl group can beoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkoxy, alkyl,cyano, halo, hydroxy, and nitro.

[0051] The term “arylalkenyl,” as used herein, represents an alkenylgroup substituted by one, two, or three aryl groups.

[0052] The term “arylalkoxy,” as used herein, represents an aryl groupattached to the parent molecular moiety through an alkoxy group.

[0053] The term “arylalkoxyalkyl,” as used herein, represents anarylalkoxy group attached to the parent molecular moiety through analkyl group.

[0054] The term “arylalkoxyalkylcarbonyl,” as used herein, represents anarylalkoxyalkyl group attached to the parent molecular moiety through acarbonyl group.

[0055] The term “arylalkoxycarbonyl,” as used herein, represents anarylalkoxy group attached to the parent molecular moiety through acarbonyl group.

[0056] The term “arylalkyl,” as used herein, represents an alkyl groupsubstituted with one, two, or three aryl groups. The alkyl part of thearylalkyl can be optionally substituted with one or two amino groups.

[0057] The term “arylalkylcarbonyl,” as used herein, represents anarylalkyl group attached to the parent molecular moiety through acarbonyl group.

[0058] The term “arylalkylidene,” as used herein, represents an arylgroup attached to the parent molecular moiety through an alkylidenegroup.

[0059] The term “arylalkylsulfanyl,” as used herein, represents anarylalkyl group attached to the parent molecular moiety through a sulfuratom.

[0060] The term “arylalkylsulfanylalkyl,” as used herein, represents anarylalkylsulfanyl group attached to the parent molecular moiety throughan alkyl group.

[0061] The term “arylalkylsulfonyl,” as used herein, represents anarylalkyl group attached to the parent molecular moiety through asulfonyl group.

[0062] The term “arylcarbonyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a carbonyl group.

[0063] The term “aryloxy,” as used herein, represents an aryl groupattached to the parent molecular moiety through an oxygen atom.

[0064] The term “aryloxyalkoxy,” as used herein, represents an aryloxygroup attached to the parent molecular moiety through an alkoxy group.

[0065] The term “aryloxyalkyl,” as used herein, represents an aryloxygroup attached to the parent molecular moiety through an alkyl group.

[0066] The term “aryloxyalkylcarbonyl,” as used herein, represents anaryloxyalkyl group attached to the parent molecular moiety through acarbonyl group.

[0067] The term “arylsulfanyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a sulfur atom.

[0068] The term “arylsulfanylalkoxy,” as used herein, represents anarylsulfanyl group attached to the parent molecular moiety through analkoxy group. The alkoxy part of the arylsulfanylalkoxy can beoptionally substituted with one or two amino groups.

[0069] The term “arylsulfanylalkyl,” as used herein, represents anarylsulfanyl group attached to the parent molecular moiety through analkyl group. The alkyl part of the arylsulfanylalkyl can be optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkoxy, alkoxycarbonyl, amino, aminoalkoxy,aminocarbonyl, arylalkoxy, azido, carboxy, cycloalkyl, halo,heterocycle, (heterocycle)alkoxy, (heterocycle)carbonyl, and hydroxy.

[0070] The term “arylsulfinyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a sulfinyl group.

[0071] The term “arylsulfinylalkyl,” as used herein, represents anarylsulfinyl group attached to the parent molecular moiety through analkyl group. The alkyl part of the arylsulfinylalkyl can be optionallysubstituted with one or two amino groups.

[0072] The term “arylsulfonyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a sulfonyl group.

[0073] The term “arylsulfonylalkyl,” as used herein, represents anarylsulfonyl group attached to the parent molecular moiety through analkyl group. The alkyl part of the arylsulfonylalkyl can be optionallysubstituted with one or two amino groups.

[0074] The term “azido,” as used herein, represents —N₃.

[0075] The term “carbonyl,” as used herein, represents —C(O)—.

[0076] The term “carboxy,” as used herein, represents —CO₂H.

[0077] The term “carboxyalkyl,” as used herein, represents a carboxygroup attached to the parent molecular moiety through an alkyl group.

[0078] The term “cyano,” as used herein, represents —CN.

[0079] The term “cyanoalkyl,” as used herein, represents a cyano groupattached to the parent molecular moiety through an alkyl group.

[0080] The term “cycloalkenyl,” as used herein, represents anon-aromatic ring system having three to ten carbon atoms and one tothree rings, wherein at least one ring is a five-membered ring with onedouble bond, a six-membered ring with one or two double bonds, a seven-or eight-membered ring with one to three double bonds, or a nine-toten-membered ring with one to four double bonds. Examples ofcycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl,norbornylenyl, and the like. The cycloalkenyl groups of this inventioncan be optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, aminoalkyl, arylalkoxy, aryloxy, arylsulfanyl,halo, haloalkoxy, haloalkyl, and hydroxy, wherein the aryl part of thearylalkoxy, the aryloxy, and the arylsulfanyl can be further optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl,and hydroxy.

[0081] The term “cycloalkenylalkyl,” as used herein, represents acycloalkenyl group attached to the parent molecular moiety through analkyl group.

[0082] The term “cycloalkyl,” as used herein, represents a saturatedring system having three to twelve carbon atoms and one to three rings.Examples of cycloalkyl groups include cyclopropyl, cyclopentyl,bicyclo(3.1.1)heptyl, adamantyl, and the like. The cycloalkyl groups ofthis invention can be optionally substituted with one, two, three, four,or five substituents independently selected from the group consisting ofalkoxy, alkoxycarbonyl, alkyl, alkylidene, amino, aminoalkoxy,aminoalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylidene,aryloxy, arylsulfanyl, a second cycloalkyl group, (cycloalkyl)alkyl,cycloalkylalkylidene, halo, haloalkoxy, haloalkyl, heterocycle,(heterocycle)alkoxy, (heterocycle)alkyl, (heterocycle)alkylidene,hydroxy, spirocycle, and spiroheterocycle; wherein the aryl; the arylpart of the arylalkenyl, the arylalkoxy, the arylalkyl, thearylalkylidene, the aryloxy, and the arylsulfanyl; the second cycloalkylgroup, the cycloalkyl part of the (cycloalkyl)alkyl and thecycloalkylalkylidine; the heterocycle; and the heterocycle part of the(heterocycle)alkoxy, the (heterocycle)alkyl, and the(heterocycle)alkylidene can be further optionally substituted with one,two, or three substituents independently selected from the groupconsisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy.

[0083] The term “cycloalkylalkoxy,” as used herein, represents acycloalkyl group attached to the parent molecular moiety through analkoxy group.

[0084] The term “(cycloalkyl)alkyl,” as used herein, represents acycloalkyl group attached to the parent molecular moiety through analkyl group.

[0085] The term “cycloalkylalkylidene,” as used herein, represents acycloalkyl group attached to the parent molecular moiety through analkylidene group.

[0086] The term “cycloalkylcarbonyl,” as used herein, represents acycloalkyl group attached to the parent molecular moiety through acarbonyl group.

[0087] The term “cycloalkyloxy,” as used herein, represents a cycloalkylgroup attached to the parent molecular moiety through an oxygen atom.

[0088] The term “formyl,” as used herein, represents —CHO.

[0089] The term “formylalkyl,” as used herein, represents a formyl groupattached to the parent molecular moiety through an alkyl group.

[0090] The term “halo,” as used herein, represents F, Cl, Br, or I.

[0091] The term “haloalkoxy,” as used herein, represents a haloalkylgroup attached to the parent molecular moiety through an oxygen atom.

[0092] The term “haloalkyl,” as used herein, represents an alkyl groupsubstituted by one, two, three, or four halogen atoms.

[0093] The term “haloalkylcarbonyl,” as used herein, represents ahaloalkyl group attached to the parent molecular moiety through acarbonyl group.

[0094] The term “heteroalkenylene,” as used herein, represents anunsaturated group of two to six atoms containing one or two heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, wherein the remaining atoms are carbon. The heteroalkylenegroups of the present invention can be attached to the parent molecularmoiety through the carbon atoms or the heteroatoms in the chain.

[0095] The term “heteroalkylene,” as used herein, represents a saturatedgroup of two to six atoms containing one or two heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur, wherein the remaining atoms are carbon. The heteroalkylenegroups of the present invention can be attached to the parent molecularmoiety through the carbon atoms or the heteroatoms in the chain.

[0096] The term “heterocycle,” as used herein, represents a monocyclic,bicyclic, or tricyclic ring system wherein one or more rings is a four-,five-, six-, or seven-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur. Monocyclic ring systems are exemplified byany 3- or 4-membered ring containing a heteroatom independently selectedfrom the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from the group consisting ofnitrogen, oxygen and sulfur. The 3- and 4-membered rings have no doublebonds, the 5-membered ring has from 0-2 double bonds and the 6- and7-membered rings have from 0-3 double bonds. Representative examples ofmonocyclic ring systems include, but are not limited to, azetidine,azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan,imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline,isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine,oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline,oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole,pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole,thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholinesulfone, thiopyran, triazine, triazole, trithiane, and the like.Bicyclic ring systems are exemplified by any of the above monocyclicring systems fused to phenyl ring, a monocyclic cycloalkyl group asdefined herein, a monocyclic cycloalkenyl group, as defined herein, oranother monocyclic heterocycle ring system. Representative examples ofbicyclic ring systems include but are not limited to, benzimidazole,benzothiazole, benzothiophene, benzoxazole, benzofuran, benzopyran,benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole,indole, indoline, indolizine, naphthyridine, isobenzofuran,isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine,pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline,tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and thelike. Tricyclic rings systems are exemplified by any of the abovebicyclic ring systems fused to a phenyl ring, a monocyclic cycloalkylgroup as defined herein, a monocyclic cycloalkenyl group as definedherein, or another monocyclic heterocycle ring system. Representativeexamples of tricyclic ring systems include, but are not limited to,acridine, carbazole, carboline, dibenzofuran, dibenzothiophene,naphthofuran, naphthothiophene, oxanthrene, phenazine, phenoxathiin,phenoxazine, phenothiazine, thianthrene, thioxanthene, xanthene, and thelike. Heterocycle groups can be attached to the parent molecular moietythrough a carbon atom or a nitrogen atom in the group.

[0097] The heterocycle groups of the present invention can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkoxycarbonyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy,alkylsulfanylalkyl, alkynyl, amino, aminoalkyl, aminoalkylcarbonyl,aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aryl, arylalkenyl,arylalkoxyalkyl, arylalkoxyalkylcarbonyl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylalkylsulfonyl, arylcarbonyl, aryloxy,aryloxyalkylcarbonyl, arylsulfanyl, arylsulfanylalkyl, arylsulfonyl,carboxy, cyano, cyanoalkyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkylcarbonyl, formyl, formylalkyl, halo, haloalkoxy, haloalkyl, asecond heterocycle, (heterocycle)alkenyl, (heterocycle)alkyl,(heterocycle)alkylcarbonyl, (heterocycle)alkylidene,heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl,nitro, oxo, spirocycle, spiroheterocycle, and —C(NH)NH₂; wherein thearyl; the aryl part of the arylalkenyl, the arylalkoxyalkyl, thearylalkoxyalkylcarbonyl, the arylalkoxycarbonyl, the arylalkyl, thearylalkylcarbonyl, the arylalkylsulfonyl, the arylcarbonyl, the aryloxy,the aryloxyalkylcarbonyl, the arylsulfanyl, the arylsulfanylalkyl, andthe arylsulfonyl; the heterocycle; and the heterocycle part of the(heterocycle)alkenyl, the (heterocycle)alkyl, the(heterocycle)alkylcarbonyl, the (heterocycle)alkylidene, theheterocyclecarbonyl, and the heterocyclecarbonylalkyl can be furtheroptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkoxy,alkoxyalkoxycarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro.

[0098] The term “(heterocycle)alkenyl,” as used herein, represents analkenyl group substituted by one, two, or three heterocycle groups. Thealkenyl part of the (heterocycle)alkenyl can be optionally substitutedwith one or two aryl groups.

[0099] The term “(heterocycle)alkoxy,” as used herein, represents aheterocycle group attached to the parent molecular moiety through analkoxy group.

[0100] The term “(heterocycle)alkyl,” as used herein, represents aheterocycle group attached to the parent molecular moiety through analkyl group.

[0101] The term “(heterocycle)alkylcarbonyl,” as used herein, representsa (heterocycle)alkyl group attached to the parent molecular moietythrough a carbonyl group.

[0102] The term “(heterocycle)alkylidene,” as used herein, represents aheterocycle group attached to the parent molecular moiety through analkylidene group.

[0103] The term “heterocyclecarbonyl,” as used herein, represents aheterocycle group attached to the parent molecular moiety through acarbonyl group.

[0104] The term “heterocyclecarbonylalkenyl,” as used herein, representsa heterocyclecarbonyl group attached to the parent molecular moietythrough an alkenyl group.

[0105] The term “heterocyclecarbonylalkyl,” as used herein, represents aheterocyclecarbonyl group attached to the parent molecular moietythrough an alkyl group:

[0106] The term “(heterocycle)oxy,” as used herein, represents aheterocycle group attached to the parent molecular moiety through anoxygen atom.

[0107] The term “(heterocycle)sulfanyl,” as used herein, represents aheterocycle group attached to the parent molecular moiety through asulfur atom.

[0108] The term “(heterocycle)sulfanylalkyl,” as used herein, representsa heterocyclesulfanyl group attached to the parent molecular moietythrough an alkyl group.

[0109] The term “hydroxy,” as used herein, represents —OH.

[0110] The term “hydroxyalkyl,” as used herein, represents a hydroxygroup attached to the parent molecular moiety through an alkyl group.

[0111] The term “nitro,” as used herein, represents —NO₂.

[0112] The term “nitrogen protecting group,” as used herein, representsgroups intended to protect an amino group against undesirable reactionsduring synthetic procedures. Common N-protecting groups comprise acylgroups such as acetyl, benzoyl, 2-bromoacetyl, 4-bromobenzoyl,tert-butylacetyl, carboxaldehyde, 2-chloroacetyl, 4-chlorobenzoyl,a-chlorobutyryl, 4-nitrobenzoyl, o-nitrophenoxyacetyl, phthalyl,pivaloyl, propionyl, trichloroacetyl, and trifluoroacetyl; sulfonylgroups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forminggroups such as benzyloxycarbonyl, benzyloxycarbonyl (Cbz),tert-butyloxycarbonyl (Boc), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, and the like.

[0113] The term “oxo,” as used herein, represents (═O).

[0114] The term “spirocycle,” as used herein, represents an alkenyleneor alkylene group in which both ends of the alkenylene or alkylene groupare attached to the same carbon of the parent molecular moiety to form abicyclic group. The spirocycle groups of the present invention can beoptionally substituted with one substituent selected from the groupconsisting of alkyl, aryl, arylalkoxyalkyl, arylalkyl, and aryloxyalkyl.

[0115] The term “spiroheterocycle,” as used herein, represents aheteroalkenylene or heteroalkylene group in which both ends of theheteroalkenylene or heteroalkylene group are attached to the same carbonof the parent molecular moiety to form a bicyclic group. Thespiroheterocycle groups of the present invention can be optionallysubstituted with one substituent selected from the group consisting ofalkyl, aryl, arylalkoxyalkyl, arylalkyl, and aryloxyalkyl.

[0116] The term “sulfinyl,” as used herein, represents —S(O)—.

[0117] The term “sulfonyl,” as used herein, represents —SO₂—.

[0118] The term “therapeutically acceptable salt,” as use herein,represents those salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like and are commensurate with a reasonable benefit/risk ratio. Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the present invention or separately byreacting a free base group with a suitable organic acid. Representativeacid addition salts include acetate, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, trifluoroacetate, undecanoate,valerate salts, and the like. Representative alkali or alkaline earthmetal salts include calcium, lithium, magnesium, potassium, sodium, andthe like, as well as non-toxic ammonium, quaternary ammonium, and aminecations, including, but not limited to, ammonium, dimethylamine,ethylamine, methylamine, tetraethylammonium, tetramethylammonium,triethylamine, trimethylamine, and the like.

[0119] Basic addition salts can be prepared during the final isolationand purification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

[0120] The present compounds can also exist as therapeuticallyacceptable prodrugs. The term “therapeutically acceptable prodrug,”refers to those prodrugs or zwitterions which are suitable for use incontact with the tissues of patients without undue toxicity, irritation,and allergic response, are commensurate with a reasonable benefit/riskratio, and are effective for their intended use. The term “prodrug,”refers to compounds which are rapidly transformed in vivo to parentcompounds of formula (I) for example, by hydrolysis in blood.

[0121] Asymmetric centers exist in the compounds of the presentinvention. These centers are designated by the symbols “R” or “S,”depending on the configuration of substituents around the chiral carbonatom. It should be understood that the invention encompasses allstereochemical isomeric forms, or mixtures thereof, which possess theability to induce apoptosis. Individual stereoisomers of compounds canbe prepared synthetically from commercially available starting materialswhich contain chiral centers or by preparation of mixtures ofenantiomeric products followed by separation such as conversion to amixture of diastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of enantiomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

[0122] According to methods of treatment, the compounds of the presentinvention can be useful for the prevention of metastases from the tumorsdescribed above either when used alone or in combination withradiotherapy and/or other chemotherapeutic treatments conventionallyadministered to patients for treating cancer. When using the compoundsof the present invention for chemotherapy, the specific therapeuticallyeffective dose level for any particular patient will depend upon factorssuch as the disorder being treated and the severity of the disorder; theactivity of the particular compound used; the specific compositionemployed; the age, body weight, general health, sex, and diet of thepatient; the time of administration; the route of administration; therate of excretion of the compound employed; the duration of treatment;and drugs used in combination with or coincidently with the compoundused. For example, when used in the treatment of solid tumors, compoundsof the present invention can be administered with chemotherapeuticagents such as alpha inteferon, COMP (cyclophosphamide, vincristine,methotrexate, and prednisone), etoposide, mBACOD (methortrexate,bleomycin, doxorubicin, cyclophosphamide, vincristine, anddexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovinrescue), doxorubicin, cyclophosphamide, taxol,etoposide/mechlorethamine, vincristine, prednisone, and procarbazine),vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate,platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan,thalidomide, SP-PG, and the like. For example, a tumor may be treatedconventionally with surgery, radiation or chemotherapy and a compound ofthe present invention subsequently administered to extend the dormancyof micrometastases and to stabilize and inhibit the growth of anyresidual primary tumor.

[0123] The compounds of the present invention can be administeredorally, parenterally, osmotically (nasal sprays), rectally, vaginally,or topically in unit dosage formulations containing carriers, adjuvants,diluents, vehicles, or combinations thereof. The term “parenteral”includes infusion as well as subcutaneous, intravenous, intramuscular,and intrasternal injection.

[0124] Parenterally administered aqueous or oleaginous suspensions ofthe compounds of the present invention can be formulated withdispersing, wetting, or suspending agents. The injectable preparationcan also be an injectable solution or suspension in a diluent orsolvent. Among the acceptable diluents or solvents employed are water,saline, Ringer's solution, buffers, dilute acids or bases, dilute aminoacid solutions, monoglycerides, diglycerides, fatty acids such as oleicacid, and fixed oils such as monoglycerides or diglycerides.

[0125] The chemotherapeutic effect of parenterally administeredcompounds can be prolonged by slowing their absorption. One way to slowthe absorption of a particular compound is administering injectabledepot forms comprising suspensions of crystalline, amorphous, orotherwise water-insoluble forms of the compound. The rate of absorptionof the compound is dependent on its rate of dissolution which is, inturn, dependent on its physical state. Another way to slow absorption ofa particular compound is administering injectable depot forms comprisingthe compound as an oleaginous solution or suspension. Yet another way toslow absorption of a particular compound is administering injectabledepot forms comprising microcapsule matrices of the compound trappedwithin liposomes, microemulsions, or biodegradable polymers such aspolylactide-polyglycolide, polyorthoesters or polyanhydrides. Dependingon the ratio of drug to polymer and the composition of the polymer, therate of drug release can be controlled.

[0126] Transdermal patches also provide controlled delivery of thecompounds. The rate of absorption can be slowed by using ratecontrolling membranes or by trapping the compound within a polymermatrix or gel. Conversely, absorption enhancers can be used to increaseabsorption.

[0127] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules.) In these solid dosage forms, theactive compound can optionally comprise diluents such as sucrose,lactose, starch, talc, silicic acid, aluminum hydroxide, calciumsilicates, polyamide powder, tableting lubricants, and tableting aidssuch as magnesium stearate or microcrystalline cellulose. Capsules,tablets and pills can also comprise buffering agents; and tablets andpills can be prepared with enteric coatings or other release-controllingcoatings. Powders and sprays can also contain excipients such as talc,silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, ormixtures thereof. Sprays can additionally contain customary propellantssuch as chlorofluorohydrocarbons or substitutes thereof.

[0128] Liquid dosage forms for oral administration include emulsions,microemulsions, solutions, suspensions, syrups, and elixirs comprisinginert diluents such as water. These compositions can also compriseadjuvants such as wetting, emulsifying, suspending, sweetening,flavoring, and perfuming agents.

[0129] Topical dosage forms include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants, and transdermal patches.The compound is mixed under sterile conditions with a carrier and anyneeded preservatives or buffers. These dosage forms can also includeexcipients such as animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc and zinc oxide, or mixturesthereof. Suppositories for rectal or vaginal administration can beprepared by mixing the compounds of the present invention with asuitable nonirritating excipient such as cocoa butter or polyethyleneglycol, each of which is solid at ordinary temperature but fluid in therectum or vagina. Ophthalmic formulations comprising eye drops, eyeointments, powders, and solutions are also contemplated as being withinthe scope of the present invention.

[0130] The total daily dose of the compounds of the present inventionadministered to a host in single or divided doses can be in amounts fromabout 0.1 to about 200 mg/kg body weight or preferably from about 0.25to about 100 mg/kg body weight. Single dose compositions can containthese amounts or submultiples thereof to make up the daily dose.

[0131] Determination of Biological Activity

[0132] Assays for the inhibition of Bcl-X_(L) were performed in 96-wellmicrotiter plates. Compounds of the present invention were diluted inDMSO to concentrations between 100 μM and 1 pM and introduced into eachcell of the plate. A mixture totaling 125 μL per well of assay buffer(20 mM phosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PEG-8000), 50 nM ofBCL-X_(L) protein (prepared according to the procedure described inScience 1997, 275, 983-986), 5 nM fluorescein-labeled BAD peptide(purchased from Synpep, Calif.), and the DMSO solution of the compoundof the present invention was shaken for 2 minutes and placed in a LJLAnalyst (LJL Bio Systems, CA). A negative control (DMSO, 5 nM BADpeptide, assay buffer) and a positive control (DMSO, 5 nM BAD peptide,50 nM BCL-X_(L), assay buffer) were used to determine the range of theassay. Polarization was measured at room temperature using a continuousFluorescein lamp (excitation 485 mM, emission 530 mM). Percentage ofinhibition was determined by (1-((mP value of well-negativecontrol)/range))×100%. IC₅₀ values were calculated using MicrosoftExcel. Compounds of the present invention have IC₅₀ values between 0.011and 10 μM and are therefore useful for inhibiting BCL-X_(L)and treatingapoptosis-mediated diseases. Preferred compounds of the presentinvention have IC₅₀ values between 0.011 and 0.5 μM, and most preferredcompounds have IC50 values between 0.011 and 0.10 μM.

[0133] Assays for the inhibition of Bcl-2 were performed in 96-wellmicrotiter plates. Compounds of the instant invention were diluted inDMSO to concentrations between 100 μM and 1 pM and introduced into eachwell of the plate. A mixture totaling 125 μL per well of assay buffer(20 mM phosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PF-68), 30 nM ofBcl-2 protein (prepared according to the procedure described in PNAS2001, 98, 3012-3017), 5 nM fluorescein-labeled BAX peptide (preparedin-house), and the DMSO solution of the compound of the instantinvention was shaken for 2 minutes and placed in a LJL Analyst (LJL BioSystems, CA). A negative control (DMSO, 5 nM BAX peptide, assay buffer)and a positive control (DMSO, 5 nM BAX peptide, 30 nM Bcl-2, assaybuffer) were used to determine the range of the assay. Polarization wasmeasured at room temperature using a continuous Fluorescein lamp(excitation 485 mM, emission 530 mM). Percentage of inhibition wasdetermined by (1-((mP value of well-negative control)/range))×100%. IC₅₀values were calculated using Microsoft Excel. Compounds of the presentinvention have IC₅₀ values between 0.102 and 10 μM and are thereforeuseful for inhibiting Bcl-2 and treating apoptosis-mediated diseases.Preferred compounds of the present invention have IC₅₀ values between0.102 and 0.5 μM, and most preferred compounds have IC50 values between0.102 and 0.0.25 μM.

[0134] Based upon the structural and functional similarity of the Bclantiapoptotic proteins, it is reasonable to expect that in addition toinducing apoptosis by the inhibition of Bcl-X_(L) and Bcl-2, the currentinvention may induce apoptosis through their action on otherantiapoptotic proteins in the Bcl family of proteins, such as Bcl-w,Bcl-b, MCL-1 and/or A1/Bfl-1.

[0135] Synthetic Methods

[0136] Abbreviations which have been used in the descriptions of thescheme and the examples that follow are: DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; PPh₃ fortriphenylphosphine; BOC for tert-butoxycarbonyl; DMAP for4-dimethylaminopyridine; EDCI for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; THF for tetrahydrofuran;TFA for trifluoroacetic acid; DMSO for dimethylsulfoxide; dba fordibenzylideneacetone; OAc for acetate; and P(t-Bu)₃ fortri-tert-butylphosphine.

[0137] The compounds and processes of the present invention will bebetter understood in connection with the following synthetic schemeswhich illustrate the methods by which the compounds of the invention maybe prepared. Starting materials can be obtained from commercial sourcesor prepared by well-established literature methods known to those ofordinary skill in the art. It will be readily apparent to one ofordinary skill in the art that the compounds defined above can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. The groups R¹, R², R³, R⁴, and R¹⁵ are asdefined above unless otherwise noted below. It will be readily apparentto one skilled in the art that the selective protection anddeprotections steps, as well as the order of the steps themselves, canbe carried out in varying order, depending on the nature of R¹, R², R³,R⁴, R¹⁵, R^(a), R^(b), and R^(c), to successfully complete the synthesesshown below.

[0138] This invention is intended to encompass compounds having formula(I) when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

[0139] As shown in Scheme 1, compounds of formula (2) (which can beprepared according to the procedures described in the schemes andexamples listed below) can be reacted with compounds of formula (3)(which can be prepared according to the procedures described in Schemes2, 3, and 1 1, or by the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001) in thepresence of a base such as triethylamine, or diisopropylethylamine; andan an activated carbonyl species such as triphosgene,p-nitrophenylchloroformate or 1,1′-carbonyldiimidazole to providecompounds of formula (I).

[0140] Scheme 2 shows the synthesis of compounds of formula (8).Compounds of formula (4) can be converted to compounds of formula (5) bytreatment with an acid such as p-toluenesulfonic acid or trifluoroaceticacid. Compounds of formula (5) can be treated with dimethylamine toprovide compounds of formula (6) which can be protected with a groupthat is selective for the primary alcohol (such as a p-methoxybenzyl;formed by treatment of compounds of formula (6) with 4-methoxybenzyl2,2,2-trichloroethanimidoate in the presence of an acid such astrifluoroacetic acid; or prepared by other methods capable of adding ap-methoxybenzyl protecting group) to provide compounds of formula (7).Compounds of formula (7) can be treated with a reducing agent such asborane, sodium borohydride, or lithium aluminum hydride to providecompounds of formula (8).

[0141] As shown in Scheme 3, compounds of formula (9) can be convertedto compounds of formula (10) by treatment with sodium hydroxide.Condensation of compounds of formula (10) with compounds of formula (8)in the presence of triphenylphosphine and DEAD or DIAD providescompounds of formula (11) which can be deprotected under conditionsknown to those of ordinary skill in the art (for example, using aqueousHCl if P is p-methoxybenzyl) to provide compounds of formula (12).Treatment with compounds of formula (12) with diphenyldisulfide in thepresence of tributylphosphine provides compounds of formula (13) whichcan be converted to compounds of formula (I) by the method shown inScheme 1.

[0142] Scheme 4 shows the synthesis of compounds of formula (21).Compounds of formula (14) can be converted to compounds of formula (15)by converting the hydroxy group to a leaving group (such as a tosylateor mesylate group; formed by treatment with p-toluenesulfonyl chlorideor methanesulfonyl chloride, respectively, in the presence of a basesuch as triethylamine or diisopropylethylamine) and treating theresulting product with thiophenol in the presence of a base such astriethylamine or diisopropylethylamine. Compounds of formula (15) can bereduced to compounds of formula (16) by treatment with a reducing agentsuch as diisobutylaluminum hydride. Condensation of compounds of formula(16) with compounds of formula (17) in the presence of a base such assodium hydride provides compounds of formula (18) which can be reducedin the presence of a reducing agent such as borane or sodiumborohydride, then deprotected under conditions known to those ofordinary skill in the art (such as treatment with trifluoroacetic acid)to provide compounds of formula (19). Compounds of formula (19) can bereacted with compounds of formula (20) in the presence of a base such asdiisopropylethylamine or triethylamine to provide compounds of formula(21), which can be converted to compounds of formula (I) under theconditions described in Scheme 1.

[0143] As shown in Scheme 5, compounds of formula (23) can be preparedby treating compounds of formula (22) with a base such as lithiumhexamethyldisilazide or lithium diisopropylamine and then treating theresulting anion with N-phenyltrifluoromethanesulfonimide to provide thevinyl triflate, which can then be coupled with hexamethylditin in thepresence of a palladium catalyst such as (PPh₃)₄Pd or PdCl₂(PPh₃)₂ toprovide the desired product.

[0144] Scheme 6 shows the preparation of compounds of formula (28).Compounds of formula (24) (where n is 0 to 5 and each R^(a) isindependently selected from the list of substituents included in thedefinition of cycloalkyl) can be treated with a base such as lithiumdiisopropylamide or lithium hexamethyldisilazide and then quenched withtrifluoromethane sulfonic anhydride orN-phenyltrifluoromethanesulfonimide to provide compounds of formula(25). Compounds of formula (25) can be coupled with compounds of formula(23) in the presence of a palladium catalyst such as (PPh₃)₄Pd orPdCl₂(PPh₃)₂ to provide compounds of formula (26). Compounds of formula(26) can be deprotected under conditions known to those of ordinaryskill in the art (such as hydrochloric acid or trifluoroacetic acid) toprovide compounds of formula (27) which can be hydrogenated in thepresence of a catalyst such as palladium on carbon to provide compoundsof formula (28). Compounds of formula (28) can be converted to compoundsof formula (I) under the conditions described in Scheme 1.

[0145] Each R^(a) can be converted to an alternative R^(a) at variouspoints in the synthesis (i.e., before or after removal of the BOCprotecting group depending on the nature of the modifiation) by methodsknown to those of ordinary skill in the art. For example, if R^(a) is anoxo group (═O) it can be reacted with a Wittig reagent (RCH₂PPh₃Br,where R is an alkyl group) to provide the tri-substituted double bond.The double bond can be hydrogenated to provide compounds where R^(a) isalkyl. In another example, if R^(a) is an oxo group, it can be reactedwith an amine in the presence of a reducing agent such as sodiumtriacetoxyborohydride to provide a compound where R^(a) is an aminogroup which can be further modified).

[0146] The preparation of compounds of formula (33) is shown in Scheme7. Compounds of formula (29) (P is a nitrogen protecting group such asbenzyl; prepared according to a procedure similar to that described inScheme 6) can be treated with CH₂(PPh₃)I and butyllithium to providecompounds of formula (30). Treatment of compounds of formula (30) withcompounds of formula (31) (where R^(b) is alkyl) in the presence ofsodium hypochlorite to provide compounds of formula (32). Deprotectionof the nitrogen can be accomplished under conditions known to those ofordinary skill in the art (for example, using α-chloroethylchloroformate to remove a benzyl group) to provide compounds of formula(33), which can be converted to compounds of formula (I) using theprocedure outlined in Scheme 1.

[0147] Scheme 8 shows the synthesis of compounds of formula (36).Compounds of formula (22) can be reated with compounds of formula (34)(P is a protecting group such as benzyl) in the presence of a reducingagent such as sodium triacetoxyborohydride to provide compounds offormula (35). Compounds of formula (35) can be converted to compounds offormula (36) (Z¹ is hydrogen) by methods known to those of ordinaryskill in the art (for example, using α-chloroethyl chloroformate toremove a benzyl group). Compounds of formula (36) where Z¹ is hydrogencan be reacted with a variety of agents such as acid chlorides,aldehydes, and sulfonyl chlorides under conditions known to those ofordinary skill in the art to provide compounds of formula (36) where Z¹is alkylcarbonyl, alkyl, or alkylsuflonyl. Deprotection of the BOC groupin compounds of formula (36) (for example, with trifluoracetic acid)provides the free amine which can then be subjected to the conditionsdescribed in Scheme 1 to provide compounds of formula (I).

[0148] Compounds of formula (41) can be prepared following the synthesisshown in Scheme 9. Compounds of formula (37) (P is a nitrogen protectinggroup such as benzyl) can be treated with compounds of formula (38) (nis 1 or 2) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to provide compounds of formula (39). Removal ofthe BOC group under conditions known to those of ordinary skill in theart (for example, trifluoroacetic acid) provides compounds of formula(40) which can be reacted with a reagent such as triphosgene or1,1′-carbonyldiimidazole to provide compounds of formula (41) where Z²is hydrogen. Compounds of formula (41) where Z² is hydrogen can betreated with groups such as alkyl halides to provide compounds offormula (41) where Z is a group such as alkyl, arylalkyl, orcycloalkylalkyl. Removal of the protecting group (P) under conditionsknown to those of ordinary skill in the art (for example, usingα-chloroethyl chloroformate to remove a benzyl group) provides the freeamine which can be reacted under the conditions described in Scheme 1 toprovide compounds of formula (I).

[0149] Compounds of formula (43) (n is 0, 1, 2, 3, 4, or 5; and eachR^(c) is independently selected from the group of substituents listedunder the definition of aryl) can be prepared by reacting compounds offormula (23) (prepared according to the procedure described in Scheme 5)can be coupled with compounds of formula (42) in the presence of apalladium catalyst such as Pd(PPh₃)₄ or PdCl₂(PPh₃)₂ to providecompounds of formula (43). The double bond can optionally behydrogenated as shown in Scheme 6. Removal of the BOC group byconditions known to those of ordinary skill in the art (for example,trifluoroacetic acid) provides the free amine which can be reacted underthe conditions described in Scheme 1 to provide compounds of formula(I).

[0150] Each R^(c) can be modified either before or after removal of theprotecting group (depending on the modification being carried out) toprovide alternative R^(c) groups. For example, if R^(c) is nitro, thenitro group can be reduced to a primary amino group using conditionsknown to those of ordinary skill in the art. The primary amino groupthus formed can be treated with an acid chloride to provide an amide orwith an aldehyde under reductive amination conditions to provide analkyl substituted amine.

[0151] Scheme 11 shows the synthesis of compounds of formula (48).Compounds of formula (44) (Z⁴ is BOC or CH₃) can be treated with astrong base such as lithium diisopropylamide or lithiumhexamethyldisilazide then treated with chloromethyl phenyl sulfide toprovide compounds of formula (45) (Z⁴ is BOC or CH₃). Coversion ofcompounds of formula (45) to compounds of formula (46) (Z⁴ is BOC orCH₃) can be accomplished by treatment with diphenyl azidophosphate andbenzyl alcohol. Treatment of compounds of formula (46) with sodiummethanethiolate provides compounds of formula (47) (Z⁴ is BOC or CH₃).Compounds of formula (47) (Z⁴ is BOC or CH₃) can be reacted withcompounds of formula (20) to provide compounds of formula (48) (Z⁴ isBOC or CH₃). Compounds of formula (48) where Z⁴ is BOC can be convertedto compounds of formula (48) where Z⁴ is hydrogen by deprotection usingconditions known to those of ordinary skill in the art (for example,trifluoroacetic acid). Compounds of formula (48) (Z⁴ is hydrogen or CH₃)can be converted to compounds of formula (I) under the conditionsdescribed in Scheme 1.

[0152] The present invention will now be described in connection withcertain preferred embodiments which are not intended to limit its scope.On the contrary, the present invention covers all alternatives,modifications, and equivalents as can be included within the scope ofthe claims. Thus, the following examples, which include preferredembodiments, will illustrate the preferred practice of the presentinvention, it being understood that the examples are for the purposes ofillustration of certain preferred embodiments and are presented toprovide what is believed to be the most useful and readily understooddescription of its procedures and conceptual aspects.

[0153] Compounds of the invention were named by ACD/ChemSketch version5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada) or were given names which appeared to be consistent with ACDnomenclature.

EXAMPLE 1N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-phenylpiperazine-1-carboxamide

[0154] A solution of N-phenylpiperazine (30 mg, 0.185 mmol) indichloromethane (2 mL) was treated with triethylamine (77 μL, 0.555mmol), cooled to 0° C., treated with triphosgene (33 mg, 0.111 mmol),warmed to room temperature, stirred for 1 hour, treated with4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001, 86 mg,0.204 mmol) and DMAP (23 mg, 0.185 mmol), stirred overnight, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 20% 2N NH₃ inmethanol/dichloromethaneto provide the desired product (46 mg, 41%). MS(ESI) m/e 613 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ 8.0-6.75 (13H, m), 4.15(1H, m), 3.59 (2H, t), 3.39 (4H, m), 3.25 (4H, m), 3.16 (2H, t), 2.88(6H, s), 2.35-2.15 (2H, m).

EXAMPLE 2N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-nitrophenyl)piperazine-1-carboxamide

[0155] A solution of4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001, 60 mg,0.142 mmol) in dichloromethane (2 mL) at room temperature was treatedwith triethylamine (59 μL, 0.426 mmol) and p-nitrophenyl chloroformate(31 mg, 0.156 mmol), stirred for 2 hours, treated with1-(4-nitrophenyl)-piperazine (35 mg, 0.169 mmol) and DMAP (17 mg, 0.142mmol), stirred overnight, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 20% 2N NH₃ inmethanol/dichloromethane) to provide the desired product (40 mg, 43%).MS (ESI) m/e 658 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ 8.5-6.75 (12H, m),4.16 (1H, m), 3.69 (2H, t), 3.59 (2H, br s), 3.47 (2H, br s), 3.37 (2H,br d), 3.24 (4H, m), 2.87 (6H, s), 2.35-2.15 (2H, m).

EXAMPLE 34-[4-(benzyloxy)phenyl]-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperazine-1-carboxamide

[0156] The desired product was prepared by substituting1-(4-benzyloxyphenyl)-piperazine for N-phenylpiperazine in Example 1. MS(ESI) m/e 719 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ 8.0-6.75 (17H, m), 5.05(2H, s), 4.18 (1H, m), 3.66 (2H, t), 3.43-3.19 (10H, m), 2.88 (6H, s),2.40-2.10 (2H, m).

EXAMPLE 4N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperazine-1-carboxamideEXAMPLE 4A 4-[(2E)-3-(4-bromophenyl)prop-2-enoyl]morpholine

[0157] A solution of cinnamic acid (1 g, 4.405 mmol) in dichloromethane(50 mL) at room temperature was treated with morpholine (422 μL, 4.846mmol), EDCI (1.015 g, 5.286 mmol), and DMAP (54 mg, 0.441 mmol), stirredovernight, and partitioned between ethyl acetate and saturated NH₄Cl.The aqueous layer was extracted with ethyl acetate (3×50 mL) and thecombined extracts were washed with brine and dried (MgSO₄), filtered,and concentrated to provide the desired product.

EXAMPLE 4B 4-[3-(4-bromophenyl)propanoyl]morpholine

[0158] A solution of Example 4A (4.405 mmol) in 1:1 ethylacetate/ethanol (50 mL) was treated with Wilkinson's catalyst (815 mg,0.880 mmol), degassed three times by freeze-thaw cycle, heated to refluxunder nitrogen atmosphere for 2 days, and cooled to room temperature.The solution was adsorbed onto silica gel and purified by flash columnchromatography with 50% ethyl acetate in hexane to provide the desiredproduct (1.024 g, 78%). ¹H NMR (300 MHz, CD₃OD) δ 7.40 (2H, d), 7.10(2H, d), 3.62 (4H, m), 3.57 (2H, t), 3.38 (2H, t), 2.94 (2H, t), 2.58(2H, t).

EXAMPLE 4C tert-butyl4-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperazine-1-carboxylate

[0159] A solution of Example 4B (400 mg, 1.342 mmol) in toluene (3.4 mL)at room temperature was treated with 1-tert-butoxycarbonylpiperazine(300 mg, 1.611 mmol), Pd₂(dba)₃ (61 mg, 0.0671 mmol), bis-tert-butylbiphenylphosphine (40 mg, 0.134 mmol) and sodium tert-butoxide (199 mg,2.013 mmol), degassed three times by freeze-thaw cycle, stirredovernight and partitioned between ethyl acetate and saturated NH₄Cl. Theaqueous layer was extracted with ethyl acetate (3×30 mL) and thecombined extracts were dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 66% acetonitrile in dichloromethane to provide the desired product(317 mg, 59%). ¹H NMR (300 MHz, CD₃OD) δ 7.12 (2H, m), 6.91 (2H, br),3.63 (8H, br), 3.53 (2H, t), 3.36 (2H, t), 3.10 (4H, br), 2.91 (2H, t),2.58 (1H, t), 1.48 (9H, s).

EXAMPLE 4D 4-[3-(4-piperazin-1-ylphenyl)propanoyl]morpholineDihydrochloride

[0160] A mixture of Example 4C (317 mg, 0.787 mmol) in 4N HCl/dioxanewas allowed to stand for 1 hour and concentrated to provide the desiredproduct.

EXAMPLE 4EN-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperazine-1-carboxamide

[0161] The desired product was prepared by substituting Example 4D for1-phenylpiperazine in Example 1. MS (ESI) m/e 754 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 8.50-6.50 (12H, m), 4.15 (1H, br), 3.60-3.28 (12H, m),3.17 (2H, s), 3.06 (2H, m), 2.95 (4H, t), 2.70 (2H, t), 2.65 (6H, s),2.54 (2H, t), 2.17 (2H, m).

EXAMPLE 5N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[4-(3-morpholin-4-ylpropyl)phenyl]piperazine-1-carboxamideEXAMPLE 5A 4-[3-(4-bromophenyl)propyl]morpholine

[0162] A solution of Example 4B (760 mg, 2.550 mmol) in THF (10 mL) atroom temperature was treated with 5M BH₃/dimethylsulfide in diethylether (2.55 mL, 12.752 mmol), stirred for 24 hours, treated with 3Naqueous HCl (10 mL), heated to reflux for 1 hour, and partitionedbetween ethyl acetate and 1N NaOH. The aqueous layer was extracted withethyl acetate (3×50 mL) and the combined extracts were dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% 2N NH₃ in methanol/dichloromethaneto provide the desired product (565 mg, 78

EXAMPLE 5B tert-butyl4-[4-(3-morpholin-4-ylpropyl)phenyl]piperazine-1-carboxylate

[0163] The desired product was prepared by substituting Example 5A forExample 4B in Example 4C. ¹H NMR (300 MHz, CDCl₃) δ 7.09 (2H, d), 6.85(2H, d), 3.73 (4H, br), 3.57 (4H, t), 3.08 (4H, t), 2.58 (2H, t), 2.44(6H, br), 1.75 (2H, br), 1.48 (9H, s).

EXAMPLE 5C 4-[3-(4-piperazin-1-ylphenyl)propyl]morpholinetris(trifluoroacetate)

[0164] A solution of Example 5B (671 mg, 1.725 mmol) in dichloromethane(2 mL) at room temperature was treated with TFA (1.8 mL) and water (0.2mL) allowed to stand for 2 hours The solution was concentrated toprovide the desired product.

EXAMPLE 5DN-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[4-(3-morpholin-4-ylpropyl)phenyl]piperazine-1-carboxamide

[0165] A suspension of4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001, 20 mg,0.0434 mmol) in THF (1.5 mL) at 0° C. was treated with NaH (8.6 mg,0.217 mmol), warmed to room temperature, stirred for 1 hour, cooled to−20° C., treated with 1,1′-carbonyldiimidazolide (7.7 mg, 0.0477 mmol),slowly warmed to room temperature over 2 hours, quenched with aceticacid (25 μL, 0.434 mmol), treated with Example 5C (30 mg, 0.0477 mmol)and triethylamine (60 μL, 0.434 mmol), stirred for 5 hours, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 20% 2N NH₃ in methanol/dichloromethaneto provide the desired product (30 mg, 94%). MS (ESI) m/e 740 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.50-6.75 (12H, m), 4.15 (1H, m), 3.74 (4H, brs), 3.45 (4H, br s), 3.30 (4H, br), 3.13 (2H, m), 2.99 (4H, br s), 2.83(2H, m), 2.73 (6H, s), 2.15 (2H, m), 1.85 (2H, m).

EXAMPLE 6N-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxamideEXAMPLE 6A tert-butyl4-[(trifluoroacetyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate

[0166] A −78° C. solution of diisopropylamine (4 mL, 28.5 mmol) in THF(10 mL) was treated with 2.5M n-butyllithium in hexanes (10 mL), stirredfor 1 hour, treated dropwise with a solution of tert-butyl4-oxopiperidine-1-carboxylate (4.67 g, 23.4 mmol) in THF (20 mL),stirred for 1 hour, treated with a solution of2-[N,N-bis(trifluoromethylsulfonyl)amino]pyridine (8.4 g, 23.4 mmol) inTHF (20 mL), and warmed to room temperature overnight. The mixture wasquenched with aqueous NH₄Cl (50 mL), and extracted with ethyl acetate(3×50 mL). The combined extracts were washed with 1N NaOH (50 mL), dried(Na₂CO₃), filtered, and concentrated. The concentrate was loaded on apad of Al₂O₃ (neutral, 100 g) and eluted with 1:9 ethyl acetate/hexanesto provide the desired product (5.73 g, 74%). MS (CI) m/e 332 (M+H)⁺,349 (M+18)⁺.

EXAMPLE 6B tert-butyl4-(4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0167] A solution of Example 6A (4.0 g, 12 mmol) and4-fluorophenylboronic acid (1.68 g, 12 mmol) in 1,2-dimethoxyethane (100mL) and methanol (50 mL) was treated withtetrakis(triphenylphosphine)palladium(0) (0.416 g, 0.36 mmol) and CsF(3.64 g, 24 mmol), heated to reflux, and stirred overnight. The reactionwas concentrated and the concentrate was dissolved in ethyl acetate (100mL) and water (50 mL). The aqueous layer was extracted with ethylacetate (2×50 mL) and the combined extracts were washed with water andbrine, dried (Na₂SO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 1:6 ethylacetate/hexanes to provide the desired product (2.6 g, 78%). MS(CI) m/e278 (M+H)⁺.

EXAMPLE 6C 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine

[0168] A solution of Example 6B (0.5 g, 1.8 mmol) in dichloromethane (5mL) at room temperature was treated with 2M HCl in diethyl ether (5 mL),stirred overnight, and concentrated to provide the desired product (0.45g, 95%). MS (ESI) m/e 178 (M+H)⁺.

EXAMPLE 6DN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxamide

[0169] The desired product was prepared by substituting Example 6C and4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001) for1-(4-nitrophenyl)-piperazine and4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide,respectively, in Example 2. MS (ESI) m/e 656.2 (M+H)⁺, 654.2 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.65 (m, 1H), 8.49(d, 1H), 8.30(d, 1H), 7.84 (dd, 1H), 7.43-7.48 (m, 4H), 7.13-7.29 (m, 7H), 6.11 (m,1H), 4.09 (m, 1H), 4.00 (m, 2H), 3.54 (m, 2H), 2.93-2.95 (m, 2H), 2.71(s, 3H), 2.69 (s, 3H), 2.66 (m, 2H), 2.46 (m, 2H), 1.75 (m, 2H), 1.61(m, 2H), 1.36 (m, 2H).

EXAMPLE 7N-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-fluorophenyl)piperidine-1-carboxamideEXAMPLE 7A tert-butyl 4-(4-fluorophenyl)piperidine-1-carboxylate

[0170] A solution of Example 6B (2 g, 7.2 mmol) in ethanol (30 mL) wastreated with 10% Pd/C (200 mg) and shaken at room temperature under 60psi of H₂ for 4 hours. The mixture was filtered and the filter cake waswashed with ethanol. The filtrate was concentrated to provide thedesired product (1.95 g, 96%). MS (CI) m/e 280 (M+H)⁺.

EXAMPLE 7B 4-(4-fluorophenyl)piperidine

[0171] The desired product was prepared by substituting Example 7A forExample 6B in Example 6C. MS (ESI) m/e 180 (M+H)⁺.

EXAMPLE 7CN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-fluorophenyl)piperidine-1-carboxamide

[0172] The desired product was prepared by substituting Example 7B and4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001) for1-(4-nitrophenyl)-piperazine and4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide,respectively, in Example 2. MS (ESI) m/e 658.2 (M+H)⁺, 656.2 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.60 (m, 1H), 8.49 (d, 1H), 8.30(d, 1H), 7.83 (dd, 1H), 7.06-7.29 (m, 9H), 4.15 (m, 1H), 4.06 (m, 2H),4.01 (m, 2H), 3.37 (m, 2H), 2.93-2.95 (m, 2H), 2.83 (m, 3H), 2.72 (s,3H), 2.70 (s, 3H), 2.66 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H), 1.36 (m,2H).

EXAMPLE 8N-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperazine-1-carboxamideEXAMPLE 8A 4,4-dimethylcyclohexanone

[0173] A solution of 4,4-dimethyl-2-cyclohexen-1-one (25.37 g, 0.204mol) in ethanol at room temperature (200 mL) was treated with 10% Pd/Ccatalyst (1.5 g) and agitated under 60 psi H₂ for 4 hours. The reactionwas filtered and the filter cake was washed with ethanol. The filtratewas concentrated to provide the desired product (22.4 g, 87%). MS (CI)m/e 127 (M+H)⁺.

EXAMPLE 8B tert-butyl 4-(4,4-dimethylcyclohexyl)piperazine-1-carboxylate

[0174] A solution of Example 8A (0.28 g, 2.2 mmol) and1-tert-butoxycarbonylpiperazine (0.42 g, 2.2 mmol) in dichloroethane (5mL) at room temperature was treated with acetic acid (100 μL) and sodiumtriacetoxyborohydride (0.53 g, 2.5 mmol), stirred overnight, dilutedwith ethyl acetate (300 mL), washed sequentially with 1N NaOH, water,and brine, dried (Na₂SO₄), filtered, and concentrated to provide thedesired product (650 mg, 95%). MS (ESI) m/e 297 (M+H)⁺.

EXAMPLE 8C 1-(4,4-dimethylcyclohexyl)piperazine

[0175] The desired product was prepared by substituting Example 8B forExample 6B in Example 6C. MS (ESI) m/e 197 (M+H)⁺.

EXAMPLE 8DN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperazine-1-carboxamide

[0176] The desired product was prepared by substituting Example 8C and4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001) for1-(4-nitrophenyl)-piperazine and4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide,respectively, in Example 2. MS (ESI) m/e 675.3 (M+H)⁺, 673.3 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.81 (m, 1H), 8.49 (d, 1H), 8.31(d, 1H), 7.82 (dd, 1H), 7.15-7.30 (m, 5H), 4.13 (m, 1H), 4.07 (m, 2H),4.02 (m, 2H), 3.07 (m, 2H), 2.95 (m, 4H), 2.71 (s, 3H), 2.69 (s, 3H),2.66 (m, 2H), 1.86-1.90 (m, 2H), 1.77 (m, 2H), 1.61 (m, 4H), 1.11-1.49(m, 4H), 0.89 (s, 6H).

EXAMPLE 9 N-55[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperazine-1-carboxamide

[0177] The desired product was prepared by substituting Example 8C for1-(4-nitrophenyl)-piperazine in Example 2. MS (ESI) m/e 647.3 (M+H)⁺,645.3 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 10.90 (s, 1H), 10.32 (m, 1H),8.49 (d, 1H), 8.30 (d, 1H), 7.81 (dd, 1H), 7.18-7.29 (m, 5H), 4.25 (m,1H), 4.04 (m, 1H), 3.88 (m, 4H), 3.46-3.52 (m, 2H), 3.40 (m, 2H),2.95-3.1 (m, 2H), 2.71 (m, 6H), 2.18 (m, 2H), 1.82 (m, 2H), 1.61 (m,2H), 1.43 (m, 2H), 1.16-1.22 (m, 2H), 0.89 (s, 6H).

EXAMPLE 10N-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4,4-dimethyl-1,4′-bipiperidine-1′-carboxamideExample 10A 4,4-dimethylpiperidine

[0178] A suspension of LiAlH₄ (5.5 g, 145 mmol) in diethyl ether (300mL) was treated in portions with 3,3-dimethylglutarimide (8.5 g, 57.7mmol), heated to reflux, stirred overnight, cooled to room temperature,and treated with 1N NaOH (70 mL). The solution was decanted and theremaining solid was washed with diethyl ether (3×200 mL). The combinedorganic washes were washed with brine, dried (Na₂SO₄), filtered, andconcentrated to a volume of 200 mL. The solution was treated with 2M HClin diethyl ether (50 mL) and the mixture was filtered and the filtercake was washed with diethyl ether (3×150 mL) to provide the desiredproduct (6.58 g, 76%). MS (CI) m/e 114 (M+H)⁺.

EXAMPLE 10B tert-butyl 4,4-dimethyl-1,4′-bipiperidine-1′-carboxylate

[0179] The desired product was prepared by substituting Example 10A andtert-butyl 4-oxo-1-piperidinecarboxylate for Example 8A and1-tert-butoxycarbonylpiperazine, respectively, in Example 8B. MS (CI)m/e 297 (M+H)⁺.

EXAMPLE 10C 4,4-dimethyl-1,4′-bipiperidine

[0180] The desired compound was prepared by substituting Example 10B forExample 6B in Example 6C. MS (ESI) m/e 197 (M+H)⁺.

EXAMPLE 10DN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4,4-dimethyl-1,4′-bipiperidine-1′-carboxamide

[0181] The desired product was prepared by substituting Example 10C and4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrobenzenesulfonamide(prepared according to the procedure described in commonly owned U.S.patent application Ser. No. 09/957,256, filed Sep. 20, 2001) for1-(4-nitrophenyl)-piperazine and4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide,respectively, in Example 2. MS (ESI) m/e 675.4 (M+H)⁺, 673.3 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.95 (m, 1H), 8.48 (d, 1H), 8.31(d, 1H), 7.81 (dd, 1H), 7.13-7.29 (m, 5H), 4.02-4.15 (m, 2H), 3.29 (m,4H), 2.97 (m, 4H), 2.75 (m, 2H), 2.71 (s, 3H), 2.69 (s, 3H), 2.10 (m,2H), 1.75 (m, 4H), 1.62 (m, 4H), 1.52 (m, 4H), 1.37 (m, 2H), 0.97 (s,6H).

EXAMPLE 114-(4-benzyl-4-methoxycyclohexyl)-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperazine-1-carboxamideEXAMPLE 11A 8-benzyl-1,4-dioxaspiro[4.5]decan-8-ol

[0182] A 0° C. solution of 2M benzylmagnesium chloride in THF (20 mL)was treated with a solution of 1,4-cyclohexanedione mono-ethylene ketal(6.24 g, 40 mmol) in THF (50 mL), warmed to room temperature, stirredovernight, quenched with saturated NH₄Cl (100 mL), and extracted withethyl acetate (3×100 mL). The combined extracts were washed with waterand brine, dried (Na₂SO₄), filtered, and concentrated. The concentratewas purified by flash column chromatography on silica gel with 6:1hexanes/ethyl acetate to provide the desired product (8.08 g, 81%). MS(CI) m/e 231(M−18)⁺, 249 (M+H)⁺, 266.2 (M+18)⁺.

EXAMPLE 11B 8-benzyl-8-methoxy-1,4-dioxaspiro[4.5]decane

[0183] A solution of Example 11A (8.08 g, 32.5 mmol) in THF (150 mL) atroom temperature was treated with 60% NaH in mineral oil (3.2 g, 80mmol), stirred for 1 hour, treated with iodomethane (5 mL, 80 mmol),stirred overnight, quenched with saturated NH₄Cl, and extracted withethyl acetate (3×200 mL). The combined extracts were washed with waterand brine, dried (Na₂SO₄), filtered, and concentrated to provide thedesired product. MS (CI) m/e 280.2 (M+18)⁺.

EXAMPLE 11C 4-benzyl-4-methoxycyclohexanone

[0184] A solution of Example 11B (8.5 g, 32.5 mmol) in acetone (200 mL)was treated with water (100 mL) and p-toluenesulfonic acid monohydrate(1 g), heated to reflux, stirred overnight, and concentrated to removethe acetone. The remaining aqueous solution was extracted with ethylacetate (3×1 00 mL) and the combined extracts were washed sequentiallywith 1N NaOH, water, and brine, dried (Na₂SO₄), filtered, andconcentrated to provide the desired product (6.95 g, 95%). MS (CI) m/e236.2 (M+18)⁺.

EXAMPLE 11D tert-butyl4-(4-benzyl-4-methoxycyclohexyl)piperazine-1-carboxylate

[0185] The desired product was prepared by substituting Example 11C forExample 8A in Example 8B. MS (ESI) m/e 389.2 (M+H)⁺.

EXAMPLE 11E 1-(4-benzyl-4-methoxycyclohexyl)piperazine

[0186] The desired product was prepared by substituting Example 11D forExample 6B in Example 6C. MS (ESI) m/e 289.2 (M+H)⁺.

EXAMPLE 11F4-(4-benzyl-4-methoxycyclohexyl)-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperazine-1-carboxamide

[0187] The desired product was prepared by substituting Example 11E for1-(4-nitrophenyl)-piperazine in Example 2. MS (ESI) m/e 739.4 (M+H)⁺,737.4 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 10.52 (s, 1H), 10.20 (m, 1H),8.49 (d, 1H), 8.29 (d, 1H), 7.80 (dd, 1H), 7.13-7.29 (m, 10H), 4.24 (m,1H), 4.00-4.05 (m, 2H), 3.40 (m, 4H), 3.22 (s, 3H), 3.14 (m, 4H), 2.92(m, 2H), 2.71 (s, 6H), 2.16 (m, 2H), 1.81 (m, 4H), 1.75 (m, 4H), 1.51(m, 2H), 1.36 (m, 2H).

EXAMPLE 12N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperidine-1-carboxamideEXAMPLE 12A 4,4-dimethylcyclohex-1-en-1-yl trifluoroacetate

[0188] The desired compound was prepared by substituting Example 8A fortert-butyl 4-oxopiperidine-1-carboxylate in Example 6A. MS(CI) m/e 258(M+H)⁺.

EXAMPLE 12B 4-(4,4-dimethylcyclohex-1-en-1-yl)pyridine

[0189] A solution of Example 12A (0.775 g. 3.0 mmol) and4-tributylstannylpyridine(1.22 g, 3.3 mmol) in 1-methyl-2-pyrrolidinone(5 mL) was treated with Pd₂(dba)₃ (55 mg, 0.06 mmol), CuI (65 mg, 0.35mmol), Ph₃P (125 mg, 0,475 mmol) and K₂CO₃ (550 mg, 3.9 mmol), purgedwith argon, and stirred for 25 hours at 90° C. The reaction mixture wasdiluted with ethyl acetate (50 mL) and saturated aqueous potassiumfluoride (10 mL), stirred 2 hoursr at room temperature, and filteredthrough a pad of diatomaceous earth (Celite®). The filtrate layers wereseparated and the organic phase was washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 4:1 ethyl acetate andhexanes to provide 200 mg (36%) of the desired product. MS(ESI) m/e188.1 (M+H)⁺.

EXAMPLE 12C 4-(4,4-dimethylcyclohexyl)piperidine Hydrochloride

[0190] A solution of Example 12B (200 mg, 1.07 mmol) in acetic acid (10mL) was treated with PtO₂ (80 mg) and stirred under 4 atm of H₂ at roomtemperature for 72 hours. The mixtre was filtered and the filtrate wasconcentrated. The concentrate was dissolved in dichloromethane (5 mL)and 2M HCl in diethyl ether (5 mL) and concentrated to provide 150 mg(72%) of the desired product. MS(ESI) m/e 196.1 (M+H)⁺.

EXAMPLE 12DN-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperidine-1-carboxamide

[0191] The desired product was prepared by substituting Example 12C for1-(4-nitrophenyl)-piperazine in Example 2. MS (ESI) m/e 646.3 (M+H)⁺,644.3 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H), 9.87 (m, 1H),8.47 (d, 1H), 8.27 (d, 1H), 7.80 (dd, 1H), 7.14-7.26 (m, 5H), 4.22 (m,1H), 3.93 (m, 2H), 3.76 (m, 4H), 3.14 (m, 2H), 2.73 (m, 4H), 2.65 (m,2H), 2.17 (m, 2H), 1.66 (m, 2H), 1.46 (m, 2H), 1.32 (m, 2H), 1.09 (m8H), 0.857 (s, 3H), 0.822 (s, 3H).

EXAMPLE 13 4-{4-[acetyl(benzyl)amino]phenyl}-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-3,6-dihydropyridine-1(2H)-carboxamideEXAMPLE 13A tert-butyl4-(trimethylstannyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0192] A solution of Example 6A (5.62 g, 16.95 mmol) in dioxane (80 mL)was treated with hexamethyldistannane (5.0 g, 15.26 mmol), lithiumchloride (4.07 g, 96.0 mmol), and tetrakis(tirphenylphosphine)palladium(0) (0.333 g, 0.288 mmol) and was stirred at reflux overnight. Themixture was cooled to room temperature, concentrated, dissolved indichloromethane (200 mL), treated with saturated aqueous KF (200 mL),stirred at room temperature for 1 hour, and filtered throughdiatomaceous earth (Celite®). The filtrate layers were separated and theorganic phase washed with water and brine, dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 10:1 hexanes/ethyl acetate to provide4.6 g (83%) of the desired product. MS(CI): m/e 348 (M+H)⁺.

EXAMPLE 13B N-benzyl-N-(4-bromophenyl)amine

[0193] A solution of 4-bromoaniline (1.76 g, 10 mmol) and benzaldehyde(1.06 g, 1 0 mmol) in dichloroethane (15 mL) was treated with NaBH(OAc)₃(2.32 g, 11 mmol) and glacial acetic acid (1 mL), stirred overnight atroom temperature, quenched with 1N NaOH, and extracted with CH₂Cl₂ (3×50mL). The combined extracts were washed with water and brine, dried,(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 5:1 hexanes/ethyl acetateto provide 2.21 g (84%) of the desired product. MS(ESI) m/e 261.9(M+H)⁺, 263.9 (M+H)⁺.

EXAMPLE 13C N-benzyl-N-(4-bromophenyl)acetamide

[0194] A solution of Example 14B (2.21 g, 8.4 mmol) in dichloromethane(50 mL) was treated with diisopropylethylamine (3 mL) and acetylchloride (3 mL), stirred at room temperature for 30 minutes, dilutedwith dichloromethane (150 mL), washed sequentially with 6N HCl, water,1N NaOH, water, and brine; dried (Na₂SO₄), filtered, and concentrated toprovide 2.47 g (97%) of the desired product. MS(ESI) m/e 303.9 (M+H)⁺,305.9 (M+H)⁺.

EXAMPLE 13D tert-butyl4-{4-[acetyl(benzyl)amino]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

[0195] A solution of Example 14A (0.346 g, 1.0 mmol) and Example 14C(0.304 g, 1.0 mmol) in dioxane (1 5 mL) was treated withtetrakis(triphenylphosphine)palladium (0) (5 8 mg, 0.05 mmol) andcuprous bromide (10 mg, 0.07 mmol) and heated to reflux under nitrogenfor 15 hours. The mixture was cooled to room temperature, concentrated,dissolved in ethyl acetate (100 mL), treated with saturated aqueous KF(10 mL) stirred at room temperature for 1 hour, and filtered throughdiatomaceous earth (Celite®). The filtrate layers were separated and theorganic phase was washed with water and brine, dried (Na₂SO₄), filtered,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10:1 hexanes/ethyl acetate to provide0.190 g (47%) of the desired product. MS(ESI) m/e 407.1 (M+H)⁺.

EXAMPLE 13E4-{4-[acetyl(benzyl)amino]phenyl}-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-3,6-dihydropyridine-1(2H)-carboxamide

[0196] A solution of Example 14D (0.095 g, 0.024 mmol) indichloromethane (2 mL) was treated with 2M HCl in diethyl ether (4 mL),stirred at room temperature for 1 hour, and concentrated. The desiredproduct was prepared by substituting this product for1-(4-nitrophenyl)-piperazine in Example 2. MS (ESI) m/e 757.3 (M+H)⁺,755.3 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.85 (m, 1H),8.51 (d, 1H), 8.28 (d, 1H), 7.84 (dd, 1H), 7.41 (d, 2H), 7.14-7.28 (m,12H), 6.18 (m, 1H), 4.85 (s, 2H), 4.20 (m, 1H), 4.00 (m, 2H), 3.51(m,2H), 3.14 (m, 2H), 2.73 (m, 6H), 2.45 (m, 2H), 2.15 (m, 2H), 1.82 (s,3H).

EXAMPLE 144-{4-[acetyl(benzyl)amino]phenyl}-N-{[4-({(R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperidine-1-carboxamideEXAMPLE 14A tert-butyl4-{4-[acetyl(benzyl)amino]phenyl}piperidine-1-carboxylate

[0197] A solution of Example 14D (0.090 g, 0.22 mmol) in methanol (10mL) was treated with 10% Pd/C (30 mg) and stirred under 1 atm hydrogenat room temperature for 2 hours, filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 2:1 hexanes/ethyl acetate to provide 0.075 g (83%) of the desiredproduct. MS(ESI) m/e 409.2 (M+H)⁺.

EXAMPLE 14B4-{4-[acetyl(benzyl)amino]phenyl}-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperidine-1-carboxamide

[0198] A solution of Example 15A in dichloromethane (2 mL) was treatedwith 2M HCl in diethyl ether (4 mL), stirred at room temperature, andconcentrated. The desired product was prepared by substituting thisproduct for 1-(4-nitrophenyl)-piperazine in Example 2. MS (ESI) m/e759.4 (M+H)⁺, 757.3 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 10.90 (s, 1H),9.82 (m, 1H), 8.50 (d, 1H), 8.39 (d, 1H), 7.82 (dd, 1H), 7.08-7.29 (m,14H), 4.82 (s, 2H), 4.21 (m, 1H), 4.01 (m, 2H), 3.14 (m, 2H), 2.73 (m,6H), 2.19 (m, 2H), 1.82 (s, 3H), 1.77 (m, 2H), 1.42 (m, 2H).

EXAMPLE 15N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[2-methoxy-4-(3-morpholin-4-ylpropyl)phenyl]piperidine-1-carboxamideEXAMPLE 15A 4-chloro-2-methoxyphenyl trifluoroacetate

[0199] A solution of 4-chloro-2-methoxyphenol (10.0 g, 63.0 mmol) inpyridine (30 mL) was cooled to 0° C., treated withtrifluoromethanesulfonic anhydride (17.8 g, 63.0 mmol), stirred 30minutes, warmed to room temperature, and stirred for 24 hours. Thereaction mixture was poured into water and extracted with ether (3×150mL). The combined extracts were washed sequentially with water, 10% HCl(2×), water, and brine; dried (Na₂SO₄), filtered, and concentrated toprovide 19.0 g of the desired product. MS(CI) m/e 290.1 (M)⁺.

EXAMPLE 15B tert-butyl4-(4-chloro-2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0200] A solution of Example 16A (0.346 g, 1.00 mmol) and Example 14A(0.290 g, 1.00 mmol) in dioxane (4 mL) was treated with LiCl (0.127 g,3.00 mmol) and Pd(Ph₃P)₄ (0.023 g, 0.020 mmol) and was heated to 105° C.overnight. The mixture was cooled to room temperature, concentrated,dissolved in ethyl acetate (100 mL), treated with saturated aqueous KF(10 mL), stirred at room temperature for 1 hour, and filtered throughtdiatomaceous earth (Celite®). The filtrate layers were separated and theorganic phase was washed with water and brine, dried (Na₂SO₄), filtered,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 6:1 hexanes/ethyl acetate to provide0.227 g (70.0%) of the desired product. MS(CI) m/e 324.1 (M)⁺.

EXAMPLE 15C tert-butyl4-{2-methoxy-4-[(1E)-3-morpholin-4-yl-3-oxoprop-1-enyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

[0201] A solution of Example 16B (0.057 g, 0.176 mmol) and4-acryloylmorpholine (0.050 g, 0.352 mmol) in dioxane (1 mL) was treatedwith Pd₂(dba)₃ (2.42 mg, 0.0026 mmol), N-methyldicyclohexaylamine (0.069g, 0.352 mmol), and P(t-Bu)₃ (0.0012 g, 0.0056 mmol) and stirred at 120°C. overnight. The mixture was cooled to room temperature, diluted withethyl acetate (100 mL), washed with water and brine, dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 20:1 dichloromethane/methanol toprovide 0.070 g (93%) of the desired product. MS(ESI) m/e 429.2 (M+1)⁺.

EXAMPLE 15D tert-butyl4-[2-methoxy-4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperidine-1-carboxylate

[0202] The desired product was prepared by substituting Example 16C forExample 14D in Example 15A. The resulting product was purified by flashcolumn chromatography on silica gel with 20:1 dichloromethane/methanolto provide the desired product. MS(ESI) m/e 433.2 (M+1)⁺.

EXAMPLE 15E tert-butyl4-[2-methoxy-4-(3-morpholin-4-ylpropyl)phenyl]piperidine-1-carboxylate

[0203] A solution of Example 16D (0.080 g, 0.185 mmol) in THF (2 mL) wastreated with 2M BH₃.Me₂S in THF (0.5 mL), stirred at room temperaturefor 3 hours, concentrated, dissolved in methanol (5 mL), stirred for 72hours at room temperature, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 20:1dichloromethane/methanol to provide 0.070 g (90%) of the desiredproduct. MS(ESI) m/e 419.2 (M+1)⁺.

EXAMPLE 15FN-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[2-methoxy-4-(3-morpholin-4-ylpropyl)phenyl]piperidine-1-carboxamide

[0204] A solution of Example 16E in dichloromethane (2 mL) was treatedwith 2M HCl in diethyl ether (4 mL), stirred at room temperature for 1hour, and concentrated. The desired product was prepared by substitutingthis product for 1-(4-nitrophenyl)-piperazine in Example 2. MS (ESI) m/e769.4 (M+H)⁺, 767.3 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 10.92 (s,1H),10.52 (m, 1H), 10.02 (m, 1H), 8.50 (d, 1H), 8.29 (d, 1H), 7.84 (dd,1H), 7.13-7.29 (m, 5H), 7.02 (d, 1H), 6.83 (d, 1H), 6.75 (dd, 1H), 4.23(m, 1H), 4.02 (m, 2H), 3.95 (m, 2H), 3.78 (s, 3H), 3.75 (m, 2H), 3.40(m, 2H), 3.14 (m, 2H), 2.73 (m, 6H), 2.60 (t, 2H), 2.19 (m, 2H), 2.00(m, 2H), 1.70 (m, 2H), 1.45 (m, 2H).

[0205] Following the procedures described in the examples and theschemes, the following compounds may be prepared:

[0206] wherein R² is one of the following structures:

[0207] A is one of the following structures:

[0208] R⁴ is one of the following structures:

[0209] It will be evident to one skilled in the art that the presentinvention is not limited to the foregoing illustrative examples, andthat it can be embodied in other specific forms without departing fromthe essential attributes thereof. It is therefore desired that theexamples be considered in all respects as illustrative and notrestrictive, reference being made to the appended claims, rather than tothe foregoing examples, and all changes which come within the meaningand range of equivalency of the claims are therefore intended to beembraced therein.

What is claimed is:
 1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein A is a five-,six-, or seven-membered non-aromatic ring containing a nitrogen atomwherein from zero to two carbon atoms are replaced by a heteroatomselected from the group consisting of nitrogen, oxygen, and sulfur; R¹is selected from the group consisting of alkyl, cyano, halo, haloalkyl,nitro, and —NR⁵R⁶; R², and R³ are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxy, alkyl, alkylcarbonyloxy,alkylsulfanyl, alkynyl, aryl, arylalkoxy, aryloxy, aryloxyalkoxy,arylsulfanyl, arylsulfanylalkoxy, cycloalkylalkoxy, cycloalkyloxy, halo,haloalkoxy, haloalkyl, heterocycle, (heterocycle)oxy, hydroxy, nitro,and —NR⁵R⁶; R⁴ is selected from the group consisting of aryl,arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl, halo, heterocycle,and (heterocycle)alkoxy; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl,alkyl, alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl,arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl,heterocycle, (heterocycle)alkyl, (heterocycle)sulfanylalkyl,hydroxyalkyl, and a nitrogen protecting group; or R⁵ and R⁶, togetherwith the nitrogen atom to which they are attached, form a ring selectedfrom the group consisting of imidazolyl, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, pyrrolyl, thiomorpholinyl, andthiomorpholinyl dioxide; and R¹⁵ is selected from the group consistingof hydrogen, alkoxy, alkyl, and halo.
 2. The compound of claim 1 whereinA is piperidinyl.
 3. The compound of claim 2 selected from the groupconsisting ofN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-fluorophenyl)piperidine-1-carboxamide;andN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4,4-dimethyl-1,4′-bipiperidine-1′-carboxamide.4. The compound of claim 1 wherein A is tetrahydropyridinyl.
 5. Thecompound of claim 4 which isN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxamide.6. The compound of claim 1 wherein A is piperazinyl.
 7. The compound ofclaim 6 wherein R⁴ is cycloalkyl.
 8. The compound of claim 7 selectedfrom the group consisting ofN-{[4-({(1R)-5-(dimethylamino)-1-[(phenylthio)methyl]pentyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperazine-1-carboxamide;N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-(4,4-dimethylcyclohexyl)piperazine-1-carboxamide;and4-(4-benzyl-4-methoxycyclohexyl)-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperazine-1-carboxamide.9. The compound of claim 6 wherein R⁴ is aryl.
 10. The compound of claim9 selected from the group consisting ofN-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-phenylpiperazine-1-carboxamide;N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-nitrophenyl)piperazine-1-carboxamide;4-[4-(benzyloxy)phenyl]-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}piperazine-1-carboxamide;N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperazine-1-carboxamide;andN-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-4-[4-(3-morpholin-4-ylpropyl)phenyl]piperazine-1-carboxamide.11. A pharmaceutical composition comprising a compound of claim 1 or atherapeutically acceptable salt thereof, in combination with atherapeutically acceptable carrier.
 12. A method of promoting apoptosisin a mammal in recognized need of such treatment comprisingadministering to the mammal a therapeutically acceptable amount of acompound of claim 1, or a therapeutically acceptable salt thereof.